The present administration of calcium as supplements or medicinal specialities to be taken orally are frequently characterised by a number of disadvantages or inferior technical properties in addition to an unfavourable consumer acceptance.
Calcium is most frequently administered as calcium carbonate as this salt contains a high load of calcium. Normally 500 mg Ca2+ equivalent to 1250 mg of calcium carbonate is administered in one dosage. Incorporating 1250 mg of calcium carbonate into a tablet to be swallowed does not represent a good administration form, as the tablet is bulky and not easy to swallow.
An increasingly used dosage form containing calcium carbonate is “a chewable tablet formulation” as this dosage form presents a more palatable choice for the patient. A further improvement is the tablet melt formulation, which disperses quickly in the mouth without the aid of chewing.
However the chewable tablets and tablet melt formulations have for a number of reasons got inferior technical properties and problems related to an unfavorable consumer acceptance.
Due to a desired high content of calcium carbonate it is often necessary to incorporate a considerable amount of excipients in order to achieve a satisfactory agglomeration to produce a granulate and subsequent a satisfactory compression to form tablets. Another reason for incorporating a fairly high proportion of excipients like soluble filler materials is also carried out in order to achieve a palatable dosage form which disperses quickly in the mouth and which does not stick to the teeth. This give rise to rather large tablets, which the patient or consumer will find difficult to take.
Another disadvantage with the present chewable tablets is that they very often contain soluble filler materials, which are quite hygroscopic. The tablets thus represent a stability problem when stored in humid conditions. This problem requires the need for unnecessary packaging in order to protect the tablets against moisture, which adds to the cost of the product.
Furthermore there is a need to produce a dosage form, which gives the patient a choice with respect to the administration of the tablet.
Elderly and young people quite often prefer dosage forms that are easily dispersed in water, thereby becoming drinkable. There is thus a need for a “multi-function” dosage form, which can be chewed, dispersed in water or which just melts in the mouth.
There is also a need for a rational and industrial method of manufacture for the production of a small and compact dosage form of calcium with multi-function properties, which does not require the use of costly excipients or the use of costly packaging materials.
Particulate matter or a granular material may be produced by a variety of production processes in pharmaceutical manufacture including high speed mixing, dry granulation or compaction, extrusion, spray drying and fluid bed processing. The most common method of granulation in pharmaceutical manufacture is by high speed mixing or high shear mixing and subsequent drying of the moist granulate in a fluid bed. This method produces a dense granulate which is appropriate for making small tablets with a high density. Fluid bed granulation is much less used as this is a more complicated process and more costly with respect to investment, process validation and running cost. The fluid bed granulation process produces a less dense granulate, which is undesirable when ordinary tablets to be swallowed are to be manufactured.
The successful formulation of calcium chewable products demands very specialized raw materials and most important a very delicate production process. The importance of combining critical characteristics of the raw materials together with a carefully selected production process has been shown for calcium chewable tablets in European Patent Application published under No. 1128815 of Nycomed Pharma AS.
This document describes a process by which the undesirably high bulk of a chewable tablet containing calcium carbonate is reduced. The reduced tablet size has been accomplished by careful selection of the physical properties of the calcium carbonate source and a fluid bed granulation and drying process. The optimal windows for the mean particle size and specific surface area were found to be 3 to 40 μm and 0.1 to 1.2 m2/g, respectively, for the preferred qualities of calcium carbonate. The choice of particle size range was especially important in order to achieve a satisfactory chewability and dispersion in the mouth where as the specific surface area was important in order to accomplish an efficient or short processing time during the granulation and drying phase in a fluid bed. The fluid bed granulation step has resulted in a very homogenous distribution of the binder, which in turn results in a rapid dispersion of the tablet when chewed but also very good consolidation properties during the tabletting step. This last property is very important for the productivity of high speed tabletting machines to ensure maximum output and a minimum demand for cleaning and maintenance of tablet tooling.
However, the use of fluid bed granulation and drying raise some problems that remain unsolved. These problems are both related to the flexibility of the composition of the fluid bed granulate and to processing problems during execution of a batch recipe.
The formulation and processing problems are laid down in the below section:                Trying to make a more compact calcium chewable formulation by reducing the amount of excipients has proved to be difficult due to unsatisfactory agglomeration resulting in a granulate which contained too much fine material. Likewise the subsequent tablet compression has been found to be difficult due to insufficient tableting properties resulting in a non-cohesive tablet with an unsatisfactory high percentage for the friability.        Reducing the level of excipients has also reduced the sensory qualities for the chewable tablet formulation resulting in a reduced customer or patient acceptance.        Regular processing problems are the adherence of a powder or granulate to inner parts of fluid bed apparatus, to the spray nozzles and air filters. Another problem has been fine powder particles being lodged beneath the product screen in the lower plenum where the inlet air passes into the fluid bed. In addition to the gradual deposition of powder layers in the expansion chamber this causes a need for regular cleaning.        During the course of a batch recipe of calcium granulate there have been problems in ensuring a satisfactory fluidization during the end of the granulation step and the beginning of the drying step. Especially during the summer season where the dehumidifying capacity is at its limits there have been problems with insufficient drying and lump formation in the product container. This causes a significant problem of granulate batches, which are not according to specification with respect to the moisture content which is too high.        
U.S. Pat. No. 5,939,091: “Method for making fast-melt tablets” by Warner Lambert Company discloses compositions and processes in order to produce fast disintegrating and fast melt tablets containing calcium carbonate.
The patent specifies the use of low density alkali metals with density in the range of 0.3 g/ml to about 0.55 g/ml as these qualifies after spray drying or compaction can be compressed into tablets which has a low density and which exhibit quick disintegration in the buccal cavity and a smooth mouth feel. Tablets produced with calcium carbonate based on a denser quality of 0.85 g/ml are described not to result in an acceptable mouth-feel.
However, U.S. Pat. No. 5,939,091 does not describe compositions, which give a fast disintegration at high loadings of calcium carbonate, and, accordingly, does not produce solutions with respect to producing small and dense tablets with rapid disintegration and good sensory properties.
WO 2004/047810 A1: “Mannose-based fast dissolving tablets” by Purdue Research Foundation gives an overview over the present technologies and patents for making fast-dissolving, fast-disintegrating or fast-melting tablets. It lists the following table for technologies used in the preparation of fast-dissolving tablets:
AdvantagesDisadvantages1. Freeze dryingDissolve within secondsHighly fragile, expensive2. MouldingLow pressure for makingPoor mechanical strengthtablets3. SublimationNo pressure for makingUse of volatile materialstablets4. DirectHigh mechanical strength,Slow disintegrationcompressionlow cost
WO 2004/047810 A1 discloses a laborious method for producing fast-disintegration tablets with mannose involving first compressing a mannose and drug powder mixture to yield a tablet with very low mechanical strength and secondly to expose this fragile tablet to water vapour or high humidity to establish liquid bridges and where the tablets were subsequently dried to yield tablets with an increased mechanical strength of 40 Newton.
U.S. Pat. No. 6,149,941: “Taste of active pharmaceutical ingredients” by Merck Patent Gesellschaft discloses a process for improving the taste of solid formulations containing one or more active ingredients. The process involves co-spray drying the active together with at least one polyol where both the active and the polyol are dissolved or dispersed in the aqueous phase before commencing the spray drying in either a spray drying equipment or in a fluid bed apparatus.
The patent further discloses that the tabletting behavior of polyols like mannitol, lactitol, isomaltol and xylitol is poor resulting in low tablet hardness, scale-off and severe friability of the tablets. Sorbitol on the other hand was found to give tablets with very good tablet hardness and tablets with particular smooth surfaces. The employment of sorbitol in the compositions from the examples in the patent was in the range of 10 to 33% which gave tablets with improved sensory properties with respect to taste and chewability.
Thus, prior art suggests that dense tablets containing calcium carbonate do not yield tablets with a quick disintegration in the buccal cavity and with an acceptable mouth feel. The prior art also indicates that when formulating chewable tablets it is important to choose a polyol like sorbitol with good mouldable properties.
Furthermore it can be stated that technologies and processes producing tablets with fast disintegration or fast melt properties very often are laborious and costly where conventional pharmaceutical processing equipment cannot be used. Fast melt formulations very often also exhibit unfavorable characteristics like having to use a high percentage of excipients, being hygroscopic and being very friable and unstable to moisture.
There is thus a need to produce an improved solid and oral dosage form containing a calcium compound with the following properties:                High loading of calcium in order to produce a small and dense tablet        Fast disintegration or fast melt properties        Good sensory properties        Multi-function properties where the tablet can be chewed, melted in the mouth or dissolved in a glass of water to be taken as a liquid dosage form        Good tablet compression characteristics to yield tablets with a high degree of mechanical strength        A robust tablet formulation which can withstand normal moisture challenges from the environment        The employment of standard pharmaceutical equipment and a short processing time.        